vatalanib in treating patients with primary or secondary myelodysplastic syndromes

Conditions: Leukemia; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

Summary: rationale: vatalanib may be effective in preventing the development of leukemia in patients who have myelodysplastic syndromes. purpose: this phase ii trial is studying vatalanib to see how well it works in treating patients with primary or secondary myelodysplastic syndromes.

objectives: primary * determine the response rate, in terms of hematologic improvement and complete and partial remission, in patients with primary or secondary (therapy-related) myelodysplastic syndromes treated with vatalanib. * determine the time to transformation to acute myeloid leukemia (at least 20% blasts) or death in patients treated with this drug. secondary * determine the safety of this drug in these patients. * determine the duration of response in patients treated with this drug. * determine the cytogenetic response rate in patients treated with this drug. * determine the overall and progression-free survival of patients treated with this drug. * determine the incidence of infections requiring antibiotics or hospitalization or bleeding requiring red blood cell transfusions in patients treated with this drug. outline: this is a multicenter study. patients are stratified\* according to risk group (low grade \[refractory anemia with or without ringed sideroblasts, refractory anemia with excess blasts-1, refractory cytopenia with multilineage dysplasia with or without ringed sideroblasts, myelodysplastic syndromes-unclassified, or chronic myelomonocytic leukemia-1\] vs high grade \[refractory anemia with excess blasts-2 or chronic myelomonocytic leukemia-2\]). note: \*stratification according to risk (low vs high) does not occur after 11/30/06. patients receive oral vatalanib once daily on days 1-28. courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. patients with a complete response (cr) receive 6 additional courses after documentation of a cr. patients are followed periodically for up to 5 years from study entry. projected accrual: approximately 144 patients will be accrued for this study within 2.5 years.

Eligibility criteria:
disease characteristics: * diagnosis of primary or secondary (therapy-related) myelodysplastic syndromes\* (mds), including the following cellular types: * refractory anemia (ra)\*\* * ra with excess blasts (raeb)-1 * ra with ringed sideroblasts\*\* * refractory cytopenia with multilineage dysplasia * refractory cytopenia with multilineage dysplasia with ringed sideroblasts\* * mds-unclassified\*\* * mds associated with isolated del (5q)\*\* * chronic myelomonocytic leukemia (cmml)-1 note: \*high-risk mds (i.e., raeb-2 or cmml-2) is closed to accrual as of 11/30/06 note: \*\*accompanied with at least 1 of the following laboratory values: hemoglobin less than 10 g/dl, platelet count less than 50,000/mm3, or absolute neutrophil count less than 1,000/mm3 * no prior leukemia (i.e., 20% or greater blasts) * no prior primary or metastatic brain tumor or carcinomatous meningitis patient characteristics: age * 18 and over performance status * who 0-2 life expectancy * not specified hematopoietic * see disease characteristics hepatic * bilirubin no greater than 1.5 times upper limit of normal (uln) * ast no greater than 2.5 times uln * aptt no greater than 1.5 times uln * inr no greater than 1.5 renal * creatinine no greater than 1.5 times uln * urine protein negative by urinalysis * protein 1+ by dipstick allowed provided total urine protein no greater than 500 mg and creatinine clearance at least 50 ml/min by 24-hour urine collection cardiovascular * no significant cardiac or vascular events within the past 6 months, including any of the following: * acute myocardial infarction * unstable angina * uncontrolled hypertension * severe peripheral vascular disease (e.g., ischemic pain at rest or nonhealing ulcers or wounds) * new york heart association class ii-iv congestive heart failure * cardiac arrhythmia * disseminated intravascular coagulation or other coagulopathies * deep vein or arterial thrombosis * no history of congenital long qtc syndrome or elongated qtc (\> 450 msec for males or 470 for females) pulmonary * no pulmonary embolism within the past 6 months other * not pregnant or nursing * negative pregnancy test * fertile patients must use effective barrier contraception during and for at least 3 months after study participation * no need for full anticoagulation within the past 6 months * no significant hemorrhage (e.g., visceral, gastrointestinal, genitourinary, or gynecological) requiring red blood cell transfusion within the past month * no known cerebral aneurysms, other cerebrovascular malformations, or cns bleeding * no unhealed fractures, wounds, or ulcers prior concurrent therapy: biologic therapy * more than 12 months since prior autologous stem cell or allogeneic transplantation * more than 6 months since prior antiangiogenic agents * more than 1 month since prior interferon for mds * more than 1 month since prior hematopoietic growth factors for mds * more than 1 month since prior epoetin alfa (epo) for mds * more than 1 month since prior thalidomide for mds * more than 1 month since prior immunotherapy for mds * no concurrent prophylactic growth factors or cytokines (e.g., filgrastim \[g-csf\], sargramostim \[gm-csf\], epo or epo-derivatives, or interleukin-11) chemotherapy * no prior low-dose antimetabolites for mds (e.g., hydroxyurea, azacitidine, or low-dose cytarabine) * more than 12 months since prior chemotherapy for another disease\* note: \*not mds or leukemia endocrine therapy * more than 1 month since prior corticosteroids for mds * more than 1 month since prior androgens for mds radiotherapy * more than 12 months since prior radiotherapy for another disease\* note: \*not mds or leukemia surgery * more than 1 month since prior surgery, including needle biopsy of visceral organs and recovered * bone marrow biopsy allowed * more than 2 weeks since prior placement of a subcutaneous or tunneled venous access device (e.g., portacath or hickman's catheter) and adequately healed other * no prior cytotoxic therapy for mds * more than 1 month since prior administration of any of the following medications for mds: * danazol * retinoids * amifostine * investigational agents * no concurrent administration of any of the following medications: * warfarin * heparin * derivatives of heparin * other anticoagulants * no concurrent grapefruit or grapefruit juice

Keywords: refractory anemia with excess blasts refractory anemia with ringed sideroblasts refractory cytopenia with multilineage dysplasia chronic myelomonocytic leukemia de novo myelodysplastic syndromes secondary myelodysplastic syndromes myelodysplastic/myeloproliferative neoplasm, unclassifiable refractory anemia previously treated myelodysplastic syndromes